EP0494817A1 - Benzisoxazole and benzisothiazole derivatives, process for their preparation and pharmaceutical compositions containing them - Google Patents

Benzisoxazole and benzisothiazole derivatives, process for their preparation and pharmaceutical compositions containing them Download PDF

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EP0494817A1
EP0494817A1 EP92400033A EP92400033A EP0494817A1 EP 0494817 A1 EP0494817 A1 EP 0494817A1 EP 92400033 A EP92400033 A EP 92400033A EP 92400033 A EP92400033 A EP 92400033A EP 0494817 A1 EP0494817 A1 EP 0494817A1
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radical
piperazin
benzisoxazole
derivatives
general formula
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EP0494817B1 (en
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Jean-Louis Peglion
Joel Vian
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ADIR SARL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to new benzisoxazole and benzisothiazole derivatives, their preparation process and the pharmaceutical compositions containing them.
  • the condensation is carried out in a particularly adequate manner by operating in an appropriate solvent such as, for example, methyl ethyl ketone, methyl isobutyl ketone, toluene or dimethylformamide in the presence of an acceptor of the acid formed during the reaction, a temperature of 20 to 150 ° C.
  • an acceptor an alkali metal carbonate such as sodium carbonate or a tertiary amine such as triethylamine can be used, for example.
  • condensation of derivatives II and IV is carried out in a particularly adequate manner by operating in an appropriate solvent such as for example methylene chloride, in the presence of carbonyldiimidazole.
  • amide V is advantageously carried out by means of a double lithium aluminum hydride, in a suitable solvent, such as, for example, ether or tetrahydrofuran.
  • a suitable solvent such as, for example, ether or tetrahydrofuran.
  • the raw materials of formulas III and IV are either known products or products prepared from known compounds, according to known methods, as indicated in the examples below.
  • the derivatives of general formula I give salts with physiologically tolerable acids. These salts are also included in the present invention.
  • the derivatives of the present invention have interesting pharmacological and therapeutic properties.
  • pharmacological tests have demonstrated that the derivatives of the invention are dopamine and serotonin antagonists and have an antipsychotic activity comparable to that of haloperidol or chlopromazine, reference substances for the evaluation of antipsychotics.
  • active doses they induce only a few side effects and in particular few extra-pyramidal effects.
  • antipsychotics generally cause very significant side effects, which limits their use.
  • the compounds of the invention therefore constitute a new class of antipsychotics useful for the treatment of schizophrenia and that of depression. They also find their application as sedative, anxiolytic, anti-aggressive and analgesic agents.
  • the present invention also relates to pharmaceutical compositions containing as active ingredient a derivative of general formula I or one of its physiologically tolerable salts, mixed or associated with a suitable pharmaceutical excipient such as, for example, glucose, lactose, talc, ethylcellulose, magnesium stearate or cocoa butter.
  • a suitable pharmaceutical excipient such as, for example, glucose, lactose, talc, ethylcellulose, magnesium stearate or cocoa butter.
  • compositions thus obtained are generally in dosage form and can contain from 0.5 to 100 mg of active principle. They may take, for example, the form of tablets, dragees, capsules, suppositories, injectable or oral solutions and be administered, as the case may be, orally, rectally or parenterally at a dose of 0.5 to 100 mg of active principle. 1 to 3 times a day.
  • the aqueous phase is made alkaline and then extracted with CH2Cl2. After drying and chromatography on silica, eluting with a methylene chloride-methanol mixture, 95-5, 0.65 g of a solid product is obtained. The latter is dissolved in 10 ml of ethanol, 0.65 ml of 3N hydrochloric ether is added thereto and the mixture is left to precipitate overnight.
  • the starting (benzocyclobutan-1-yl) methyl iodide was itself prepared as follows: 6 g of benzocyclobutan-1-yl methyl para-toluenesulfonate [prepared according to the method described in JACS (1975), 154 , p 347] are mixed with 6.2 g of sodium iodide in 85 ml of acetone. The reaction medium is brought to reflux for 8 hours then poured into 150 ml of water and extracted several times with ethyl ether.
  • the starting N (6-fluoro 1,2-benzisoxazol-3-yl) piperazine was prepared according to JP YEVICH and Coll. J. Med. Chem. (1986) 29 p 359-369.
  • the starting (4,5-dimethoxybenzocyclobutan-1-yl) carboxylic acid was prepared according to the method described in Tétrahedron (1973), 29 , p 73.
  • serum + IP serum 1 animal (serum control); solvent + methylphenidate at 40 mg / kg PI: 2 animals (methylphenidate control at 40 mg / kg PI) and solvent + methylphenidate at 0.16; 0.63; 2.5 or 10 mg / kg PI: 1 animal (methylphenidate controls 0.16; 0.63; 2.5 or 10 mg / kg PI).
  • the products studied were administered at given times before injection at T0 of 40 mg / kg I.P. of methylphenidate. Each animal is observed for 10 seconds. Behavioral observations were made 30 minutes after the methylphenidate treatment. A total of 10 observation periods are carried out for each rat at time T30 mn. During these observations, the presence (1) or absence (0) of stereotypy is noted.
  • the average effective doses are listed in the table below, that is to say the doses allowing a 50% inhibition of the chewing.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • General Health & Medical Sciences (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
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Abstract

New benzisoxazole and benzisothiazole derivatives usable as medication and corresponding to the formula: <IMAGE> in which:   - each of X1, X2, X3, X4 and X5, which are identical or different, is: hydrogen, halogen, [(C1-C5)-alkyl, -alkoxy or -alkylthio], hydroxyl, acyloxy, trifluoromethyl, nitro, amino or acetamido, or   - two of them, in adjacent position, together form a methylenedioxy, ethylenedioxy or vinylenedioxy radical;   - R1 is hydrogen or C1-C5 alkyl;   - each of m and n denotes zero, one, two or three on condition that m + n is >/= 1;   - p is zero or an integer from 1 to 6;   - q is two or three and   - Y is oxygen or S(O)z, z being zero, one or two; in racemic and optically active form. <??>These derivatives and their physiologically tolerable salts can be employed in therapeutics as sedative, anxiolytic, antiaggressive and analgesic agents and for the treatment of schizophrenia and of depression.

Description

La présente invention a pour objet de nouveaux dérivés de benzisoxazole et de benzisothiazole, leur procédé de préparation et les compositions pharmaceutiques les renfermant.The present invention relates to new benzisoxazole and benzisothiazole derivatives, their preparation process and the pharmaceutical compositions containing them.

Elle concerne particulièrement les dérivés de formule générale I :

Figure imgb0001

dans laquelle :

  • X₁, X₂, X₃, X₄ et X₅ :
    • identiques ou différents représentent chacun : un atome d'hydrogène, un atome d'halogène, un radical alkyle, alkoxy ou alkythio dans chacun desquels la partie alkyle renferme de 1 à 5 atomes de carbone en chaine droite ou ramifiée, un radical hydroxy, un radical acyloxy, un radical trifluorométhyle, un radical nitro, un radical amino ou un radical acétamido, ou
    • deux d'entre eux pris en position adjacente forment ensemble un radical méthylènedioxy, un radical éthylènedioxy ou un radical vinylènedioxy ;
  • R₁ représente un atome d'hydrogène ou un radical alkyle en chaine droite ou ramifiée contenant de 1 à 5 atomes de carbone ;
  • m et n représentent chacun les valeurs zéro, un, deux ou trois à condition que m + n soit ≧ 1 ;
  • p représente zéro ou un nombre entier de 1 à 6 ;
  • q représente deux ou trois, et
  • Y représente un atome d'oxygène ou le groupe S(O)z dans lequel z prend les valeurs zéro, un ou deux ; sous forme racémique et optiquement actives.
It particularly concerns the derivatives of general formula I:
Figure imgb0001
in which :
  • X₁, X₂, X₃, X₄ and X₅:
    • identical or different each represents: a hydrogen atom, a halogen atom, an alkyl, alkoxy or alkythio radical in each of which the alkyl part contains from 1 to 5 carbon atoms in a straight or branched chain, a hydroxy radical, a acyloxy radical, a trifluoromethyl radical, a nitro radical, an amino radical or an acetamido radical, or
    • two of them taken in adjacent position together form a methylenedioxy radical, an ethylenedioxy radical or a vinylenedioxy radical;
  • R₁ represents a hydrogen atom or a straight or branched chain alkyl radical containing from 1 to 5 carbon atoms;
  • m and n each represent the values zero, one, two or three provided that m + n is ≧ 1;
  • p represents zero or an integer from 1 to 6;
  • q represents two or three, and
  • Y represents an oxygen atom or the group S (O) z in which z takes the values zero, one or two; in racemic and optically active form.

L'état antérieur de la technique dans ce domaine est illustré notamment :

  • a) soit par des publications concernant des 1,2-benzisoxazole ou benzisothiazole substitués en position 3 par un radical 4-pipéridyl lui-même N-substitué ; de tels composés sont décrits comme ayant des propriétés antipsychotiques -cf les demandes de brevet E.P. 196.132, E.P. 314.098 et les brevets US 4.352.811 et 4.812.461- ou des propiétés analgésiques ou neuroleptiques -cf les brevets US 4.469.869, US 4.355.037, la demande de brevet E.P. 080.104 et J.Med. Chem (1985) 28 p. 761-769 ;
  • b) soit par des publications concernant des 1,2-benzisothiazole substitués en position 3 par un radical N-pipérazinyl lui-même N'-substitué, pour lesquels est mentionnée soit une activité analgésique non opiacée -cf le brevet G.B 2.163.432 soit une activité anxiolytique ou antipsychotique -cf notamment les brevets E.P. 318.983, E.P. 329.168 et BE 900.555.
The prior art in this field is illustrated in particular:
  • a) either by publications concerning 1,2-benzisoxazole or benzisothiazole substituted in position 3 by a 4-piperidyl radical itself N-substituted; such compounds are described as having antipsychotic properties - see patent applications EP 196.132, EP 314.098 and US patents 4,352,811 and 4,812,461 - or analgesic or neuroleptic properties - see US patents 4,469,869, US 4,355 .037, patent application EP 080.104 and J. Med. Chem (1985) 28 p. 761-769;
  • b) or by publications concerning 1,2-benzisothiazole substituted in position 3 by an N-piperazinyl radical itself N'-substituted, for which is mentioned either a non-opioid analgesic activity -cf the patent GB 2,163,432 or an anxiolytic or antipsychotic activity -cf in particular the patents EP 318,983, EP 329,168 and BE 900,555.

Toutefois, aucun de ces documents ne suggère les produits objets de la présente invention, lesquels constituent une nouvelle classe d'antipsychotiques particulièrement intéressante du fait de la quasi innocuité de ces produits aux doses actives, en ce qui concerne les effets secondaires et notamment les effets extra-pyramidaux ; alors qu'il est connu que les antipsychotiques peuvent provoquer des effets secondaires très importants ce qui limite leur utilisation.However, none of these documents suggests the products which are the subject of the present invention, which constitute a new class of antipsychotics which is particularly advantageous because of the almost harmlessness of these products at active doses, as regards the side effects and in particular the effects. extra-pyramidal; while it is known that antipsychotics can cause very significant side effects which limits their use.

La présente invention a également pour objet le procédé de préparation des dérivés de formule générale I, caractérisé en ce que l'on condense :

  • un dérivé de formule générale II :
    Figure imgb0002
     dans laquelle q, Y, X₄ et X₅ ont les significations précédemment définies, avec
  • un dérivé de formule générale III :
Figure imgb0003
dans laquelle :
  • X₁, X₂, X₃, R₁, m, n et p ont les significations précédemment définies
    et
  • X représente un atome d'halogène, un radical mésyloxy ou un radical tosyloxy.
The present invention also relates to the process for the preparation of the derivatives of general formula I, characterized in that one condenses:
  • a derivative of general formula II:
    Figure imgb0002
     in which q, Y, X₄ and X₅ have the meanings previously defined, with
  • a derivative of general formula III:
Figure imgb0003
in which :
  • X₁, X₂, X₃, R₁, m, n and p have the meanings previously defined
    and
  • X represents a halogen atom, a mesyloxy radical or a tosyloxy radical.

La condensation s'effectue de façon particulièrement adéquate en opérant dans un solvant approprié tel que, par exemple, la méthyléthylcétone, la méthylisobutylcétone, le toluène ou le diméthylformamide en présence d'un accepteur de l'acide formé au cours de la réaction, à une température de 20 à 150 °C. Comme accepteur, on peut employer, par exemple, un carbonate de métaux alcalins comme le carbonate de sodium ou une amine tertiaire comme la triéthylamine.The condensation is carried out in a particularly adequate manner by operating in an appropriate solvent such as, for example, methyl ethyl ketone, methyl isobutyl ketone, toluene or dimethylformamide in the presence of an acceptor of the acid formed during the reaction, a temperature of 20 to 150 ° C. As an acceptor, an alkali metal carbonate such as sodium carbonate or a tertiary amine such as triethylamine can be used, for example.

De plus, les dérivés de formule générale I dans laquelle p prend les valeurs autres que zéro, c'est à dire les dérivés répondant plus précisément à la formule générale I′:

Figure imgb0004

dans laquelle :

  • X₁, X₂, X₃, X₄, X₅, R₁, m, n, q et Y ont les significations précédemment définies et
  • p′ représente un nombre entier de 1 à 6,
    ont également été préparés selon une variante du procédé précédent, caractérisée en ce que :
  • l'on condense :
    • un dérivé de formule générale II précédemment définie, avec,
    • un dérivé de formule générale IV :
    Figure imgb0005
     dans laquelle X₁, X₂, X₃, X₄, X₅, R₁, m, n et p′ ont les significations précédemment défines ; et
  • l'on réduit l'amide ainsi obtenue de formule générale V :
Figure imgb0006
dans laquelle X₁, X₂, X₃, X₄, X₅, R₁, m, n, p′, q et Y ont les significations précédemment définies.In addition, the derivatives of general formula I in which p takes the values other than zero, that is to say the derivatives corresponding more precisely to the general formula I ′:
Figure imgb0004
in which :
  • X₁, X₂, X₃, X₄, X₅, R₁, m, n, q and Y have the meanings previously defined and
  • p ′ represents an integer from 1 to 6,
    were also prepared according to a variant of the previous process, characterized in that:
  • we condense:
    • a derivative of general formula II previously defined, with,
    • a derivative of general formula IV:
    Figure imgb0005
     in which X₁, X₂, X₃, X₄, X₅, R₁, m, n and p ′ have the meanings previously defined; and
  • the amide thus obtained of general formula V is reduced:
Figure imgb0006
in which X₁, X₂, X₃, X₄, X₅, R₁, m, n, p ′, q and Y have the meanings previously defined.

La condensation des dérivés II et IV s'effectue de façon particulièrement adéquate en opérant dans un solvant approprié comme par exemple le chlorure de méthylène, en présence de carbonyldiimidazole.The condensation of derivatives II and IV is carried out in a particularly adequate manner by operating in an appropriate solvent such as for example methylene chloride, in the presence of carbonyldiimidazole.

La réduction de l'amide V s'effectue avantageusement au moyen d'un hydrure double de lithium-aluminium, dans un solvant adéquat, comme par exemple l'éther ou le tétrahydrofurane.The reduction of amide V is advantageously carried out by means of a double lithium aluminum hydride, in a suitable solvent, such as, for example, ether or tetrahydrofuran.

Ce dernier procédé de préparation des dérivés I′ est également inclus dans la présente invention.This latter process for the preparation of derivatives I ′ is also included in the present invention.

De plus, les amides de formule générale V sont des produits intermédiaires nouveaux qui font, à ce titre, partie de la présente invention.In addition, the amides of general formula V are new intermediate products which, as such, form part of the present invention.

Les amines de départ de formule générale II ont été préparées par analogie avec la synthèse décrite par J.P. YEVICH et Coll. J. Med Chem. (1986), 29, 359-369.The starting amines of general formula II were prepared by analogy with the synthesis described by JP YEVICH et al. J. Med Chem. (1986), 29 , 359-369.

Les matières premières de formules III et IV sont soit des produits connus, soit des produits préparés à partir de composés connus, selon des procédés connus, comme indiqué dans les exemples ci-après.The raw materials of formulas III and IV are either known products or products prepared from known compounds, according to known methods, as indicated in the examples below.

Les dérivés de formule générale I donnent des sels avec les acides physiologiquement tolérables. Ces sels sont également inclus dans la présente invention.The derivatives of general formula I give salts with physiologically tolerable acids. These salts are also included in the present invention.

Les dérivés de la présente invention possèdent des propriétés pharmacologiques et thérapeutiques intéressantes. En effet, les essais pharmacologiques ont démontré que les dérivés de l'invention sont des antagonistes de la dopamine et de la sérotonine et possèdent une activité antipsychotique comparable à celle de l'halopéridol ou de la chlopromazine, substances de référence pour l'évaluation des antipsychotiques. De plus, aux doses actives, ils n'induisent que peu d'effets secondaires et notamment peu d'effets extra-pyramidaux.The derivatives of the present invention have interesting pharmacological and therapeutic properties. In fact, pharmacological tests have demonstrated that the derivatives of the invention are dopamine and serotonin antagonists and have an antipsychotic activity comparable to that of haloperidol or chlopromazine, reference substances for the evaluation of antipsychotics. In addition, at active doses, they induce only a few side effects and in particular few extra-pyramidal effects.

Or il est connu que les antipsychotiques provoquent généralement des effets secondaires très importants, ce qui limite leur utilisation. Les composés de l'invention constituent donc une nouvelle classe d'antipsychotiques utiles pour le traitement de la schizophrénie et celui de la dépression. Ils trouvent aussi leur application comme agents sédatifs, anxiolytiques, anti-agressifs et analgésiques.However, it is known that antipsychotics generally cause very significant side effects, which limits their use. The compounds of the invention therefore constitute a new class of antipsychotics useful for the treatment of schizophrenia and that of depression. They also find their application as sedative, anxiolytic, anti-aggressive and analgesic agents.

La présente invention a également pour objet les compositions pharmaceutiques contenant comme principe actif un dérivé de formule générale I ou un de ses sels physiologiquement tolérables, mélangé ou associé à un excipient pharmaceutique approprié comme par exemple le glucose, le lactose, le talc, l'éthylcellulose, le stéarate de magnésium ou le beurre de cacao.The present invention also relates to pharmaceutical compositions containing as active ingredient a derivative of general formula I or one of its physiologically tolerable salts, mixed or associated with a suitable pharmaceutical excipient such as, for example, glucose, lactose, talc, ethylcellulose, magnesium stearate or cocoa butter.

Les compositions pharmaceutiques ainsi obtenues se présentent généralement sous forme dosée et peuvent contenir de 0,5 à 100 mg de principe actif. Elles peuvent revêtir, par exemple, la forme de comprimés, dragées, gélules, suppositoires, solutions injectables ou buvables et être, selon les cas, administrées par voie orale, rectale ou parentérale à la dose de 0,5 à 100 mg de principe actif 1 à 3 fois par jour.The pharmaceutical compositions thus obtained are generally in dosage form and can contain from 0.5 to 100 mg of active principle. They may take, for example, the form of tablets, dragees, capsules, suppositories, injectable or oral solutions and be administered, as the case may be, orally, rectally or parenterally at a dose of 0.5 to 100 mg of active principle. 1 to 3 times a day.

Les exemples suivants illustrent la présente invention, les points de fusion étant déterminés à la platine chauffante de Kofler sous microscope.The following examples illustrate the present invention, the melting points being determined using a Kofler heating plate under a microscope.

Exemple 1 : Example 1 : (R,S) 3-{1-[(benzocyclobutan-1-yl)méthyl]pipérazin-4-yl} 6-fluoro 1,2- benzisoxazole(R, S) 3- {1 - [(benzocyclobutan-1-yl) methyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole

Figure imgb0007
Figure imgb0007

On mélange 4 g (16.10⁻³ mole) d'iodure de (benzocyclobutan-1-yl)méthyle, 3,6 g (16.10⁻³ mole) de N-(6-fluoro 1,2-benzisoxazol-3-yl)pipérazine, 3,5 g (32.10⁻³ mole) de Na₂CO₃ et 70 ml de méthylisobutylcétone, et chauffe le tout à 80 °C pendant 12 heures sous agitation. On concentre le mélange réactionnel à l'évaporateur rotatif, reprend le concentrat par l'acétate d'éthyle. Après lavage à l'eau on extrait la phase organique, plusieurs fois, avec une solution normale d'acide chlorhydrique. On alcalinise la phase aqueuse puis l'extrait au CH₂Cl₂. Après séchage et chromatographie sur silice en éluant avec le mélange chlorure de méthylène-méthanol, 95-5, on obtient 0,65 g d'un produit solide. On dissout ce dernier dans 10 ml d'éthanol, y ajoute 0,65 ml d'éther chlorhydrique 3N et laisse précipiter durant une nuit. On recueille 0,55 g de chlorhydrate de (R,S) 3-{1-[(benzocyclobutan-1-yl)méthyl]pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole
P.F. : 246-250°C (avec sublimation vers 190°C)
Rendement : 9%
RMN (solvant : DMSO d 6)
massif échangeable par D₂O à 11,6 ppm ;
8,15 ppm, 1H (dd) ; 7,6 ppm, 1H (dd) ; 7,1 à 7,3 ppm, 5H (m) ;
4 à 4,3 ppm, 2H (d large) + 1 H (m) ; 3,1 à 3,8 ppm, 10H (m).4 g (16.10⁻³ mole) of (benzocyclobutan-1-yl) methyl iodide, 3.6 g (16.10⁻³ mole) of N- (6-fluoro 1,2-benzisoxazol-3-yl) are mixed piperazine, 3.5 g (32.10⁻³ mole) of Na₂CO₃ and 70 ml of methylisobutylketone, and the whole is heated to 80 ° C for 12 hours with stirring. The reaction mixture is concentrated on a rotary evaporator, the concentrate is taken up in ethyl acetate. After washing with water, the organic phase is extracted several times with a normal solution of hydrochloric acid. The aqueous phase is made alkaline and then extracted with CH₂Cl₂. After drying and chromatography on silica, eluting with a methylene chloride-methanol mixture, 95-5, 0.65 g of a solid product is obtained. The latter is dissolved in 10 ml of ethanol, 0.65 ml of 3N hydrochloric ether is added thereto and the mixture is left to precipitate overnight. 0.55 g of (R, S) 3- {1 - [(benzocyclobutan-1-yl) methyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole hydrochloride is collected
PF: 246-250 ° C (with sublimation around 190 ° C)
Yield: 9%
NMR (solvent: DMSO d 6)
solid exchangeable with D₂O at 11.6 ppm;
8.15 ppm, 1H (dd); 7.6 ppm, 1H (dd); 7.1 to 7.3 ppm, 5H (m);
4 to 4.3 ppm, 2H (broad d) + 1H (m); 3.1 to 3.8 ppm, 10H (m).

L'iodure de (benzocyclobutan-1-yl)méthyle de départ a lui-même été préparé comme suit : 6 g de para-toluènesulfonate de benzocyclobutan-1-yl méthyle [préparé selon le procédé décrit dans JACS (1975), 154, p 347] sont mélangés avec 6,2 g d'iodure de sodium dans 85 ml d'acétone. Le milieu réactionnel est porté à reflux pendant 8 heures puis coulé sur 150 ml d'eau et extrait plusieurs fois à l'éther éthylique. La phase organique est ensuite lavée avec une solution normale de thiosulfate de sodium, séchée sur sulfate de magnésium anhydre et concentrée pour obtenir l'iodure de (benzocyclobutan-1-yl)méthyle, sous forme d'huile .
Rendement : 88%.
Spectre RMN du proton (solvant : CDCl₃) :
2,85 ppm d, 1H ; 3,3 à 3,6 ppm m, 3H ; 3,9 ppm, m, 1H ;
7 à 7,3 ppm, m, 4H.The starting (benzocyclobutan-1-yl) methyl iodide was itself prepared as follows: 6 g of benzocyclobutan-1-yl methyl para-toluenesulfonate [prepared according to the method described in JACS (1975), 154 , p 347] are mixed with 6.2 g of sodium iodide in 85 ml of acetone. The reaction medium is brought to reflux for 8 hours then poured into 150 ml of water and extracted several times with ethyl ether. The organic phase is then washed with a normal sodium thiosulphate solution, dried over anhydrous magnesium sulphate and concentrated to obtain methyl (benzocyclobutan-1-yl) iodide, in the form of an oil.
Yield: 88%.
Proton NMR spectrum (solvent: CDCl₃):
2.85 ppm d , 1H; 3.3 to 3.6 ppm m , 3H; 3.9 ppm, m , 1H;
7 to 7.3 ppm, m , 4H.

La N(6-fluoro 1,2-benzisoxazol-3-yl)pipérazine de départ a été préparée selon J.P. YEVICH et Coll. J. Med. Chem. (1986) 29 p 359-369.The starting N (6-fluoro 1,2-benzisoxazol-3-yl) piperazine was prepared according to JP YEVICH and Coll. J. Med. Chem. (1986) 29 p 359-369.

De la même façon, ont été préparés les dérivés objets des exemples 2 et 3.In the same way, the object derivatives of Examples 2 and 3 were prepared.

Exemples 2 et 3 : Examples 2 and 3 :

  • 2) Le (R,S) 3-{1-[4-(benzocyclobutan-1-yl)butyl]pipérazin-4-yl} 1,2-benzisothiazole, et son chlorhydrate P.F (instantané) : 202 °C, à partir du bromure de 4-(benzocyclobutan-1-yl)butyle et de N-(1,2-benzisothiazol-3-yl)pipérazine.2) (R, S) 3- {1- [4- (benzocyclobutan-1-yl) butyl] piperazin-4-yl} 1,2-benzisothiazole, and its hydrochloride PF (instantaneous): 202 ° C., at from 4- (benzocyclobutan-1-yl) butyl bromide and N- (1,2-benzisothiazol-3-yl) piperazine.
  • 3) Le (R,S) 3-{1-[2-(benzocyclobutan-1-yl)éthyl]pipérazin-4-yl} 1,2-benzisothiazole et son chlorhydrate P.F (instantané) : 222 °C, à partir du bromure de 2-(benzocyclobutan-1-yl) éthyle et de N-(1,2-benzisothiazol-3-yl)pipérazine.3) (R, S) 3- {1- [2- (benzocyclobutan-1-yl) ethyl] piperazin-4-yl} 1,2-benzisothiazole and its hydrochloride PF (instant): 222 ° C, from 2- (benzocyclobutan-1-yl) ethyl bromide and N- (1,2-benzisothiazol-3-yl) piperazine.
Exemple 4 : Example 4 : (R,S) 3-{1-[(benzocyclobutan-1-yl) méthyl] pipérazin-4-yl} 1,2-benzisothiazole(R, S) 3- {1 - [(benzocyclobutan-1-yl) methyl] piperazin-4-yl} 1,2-benzisothiazole

Figure imgb0008

Un mélange de 2,5 g de tosylate de (benzocyclobutan-1-yl)méthyle [préparé selon le procédé décrit dans JACS (1975) 154, p 37], 1,9 g de N-(1,2-benzisothiazol-3-yl)pipérazine [préparée selon J.P.YEVICH et Coll. J. Med. Chem. (1986), 29, p 359-369] et de 1,3 ml de triéthylamine est porté puis maintenu au reflux dans 25 ml de toluène pendant 18 heures. Après refroidissement, on y ajoute 25 ml d'acétate d'éthyle et 20 ml de solution d'hydroxyde de sodium à 20 %. On décante, sèche la phase organique et évapore à sec. Le résidu obtenu est chromatographié sur 300 g de silice en éluant par un mélange de chlorure de méthylène/acétate d'éthyle (90/10). On obtient 1,4 g de produit (Rendement ; 40 %) qui mis dans 5 ml d'acétonitrile puis additionné de 3 ml d'éther chlorhydrique donne le dichlorhydrate de (R,S) 3-{1-[(benzocyclobutan-1-yl)méthyl]pipérazin-4-yl} 1,2-benzisothiazole, P.F. : 208-215°C (avec sublimation lente à partir de 170°C).
RMN (solvant DMSO d6)
8,15 ppm, m, 2H ; 7,4 à 7,6 ppm, m, 2H ;
7 à 7,3 ppm, m, 4H ; 4 à 4,2 ppm, d + m, 3H ;
3,2 à 3,8 ppm, m + d + m + n + m = 9H ;
3,15 ppm, d, 1H ; 11,5 ppm, 2H échangeables.
Figure imgb0008
A mixture of 2.5 g of (benzocyclobutan-1-yl) methyl tosylate [prepared according to the method described in JACS (1975) 154 , p 37], 1.9 g of N- (1,2-benzisothiazol-3 -yl) piperazine [prepared according to JPYEVICH et al. J. Med. Chem. (1986), 29 , p 359-369] and 1.3 ml of triethylamine is brought to and then maintained at reflux in 25 ml of toluene for 18 hours. After cooling, 25 ml of ethyl acetate and 20 ml of 20% sodium hydroxide solution are added thereto. Decanted, the organic phase is dried and evaporated to dryness. The residue obtained is chromatographed on 300 g of silica, eluting with a mixture of methylene chloride / ethyl acetate (90/10). 1.4 g of product are obtained (Yield; 40%) which, put in 5 ml of acetonitrile and then added with 3 ml of hydrochloric ether gives (R, S) 3- {1 - [(benzocyclobutan-1) dihydrochloride -yl) methyl] piperazin-4-yl} 1,2-benzisothiazole, mp: 208-215 ° C (with slow sublimation from 170 ° C).
NMR (DMSO d6 solvent)
8.15 ppm, m, 2H; 7.4 to 7.6 ppm, m, 2H;
7 to 7.3 ppm, m, 4H; 4 to 4.2 ppm, d + m, 3H;
3.2 to 3.8 ppm, m + d + m + n + m = 9H;
3.15 ppm, d, 1H; 11.5 ppm, 2H exchangeable.

De la même façon ont été préparés les dérivés objets des exemples 5 à 16.In the same way, the derivatives object of Examples 5 to 16 were prepared.

Exemples 5 à 16 : Examples 5 to 16 :

  • 5) Le (R,S) 3-{1-[(benzocyclobutan-1-yl)méthyl] homopipérazin-4-yl} 1,2-benzisothiazole et son di(dibenzoyltartrate) P.F. : 110-115°C, (Rendement : 52,7 %), à partir du tosylate de (benzocyclobutan-1-yl) méthyle et de la N-(1,2 benzisothiazol-3-yl) homopipérazine [elle-même préparée selon J.P. YEVICH et Coll. J. Med. Chem. (1986), 29, 359-369]. 5) (R, S) 3- {1 - [(benzocyclobutan-1-yl) methyl] homopiperazin-4-yl} 1,2-benzisothiazole and its di (dibenzoyltartrate) PF: 110-115 ° C, (Yield : 52.7%), from methyl (benzocyclobutan-1-yl) tosylate and N- (1,2 benzisothiazol-3-yl) homopiperazine [itself prepared according to JP YEVICH et al. J. Med. Chem. (1986), 29 , 359-369].
  • 6) Le (R,S) 3-{1-[(benzocyclobutan-1-yl) méthyl] pipérazin-4-yl} 1,2-benzisoxazole et son chlorhydrate P.F. : 239-243°C (avec sublimation à partir de 190°C) (Rendement : 11 %), à partir du tosylate de (benzocyclobutan-1-yl)méthyle et de la N-(1,2-benzisoxazol-3-yl) pipérazine. 6) (R, S) 3- {1 - [(benzocyclobutan-1-yl) methyl] piperazin-4-yl} 1,2-benzisoxazole and its hydrochloride PF: 239-243 ° C (with sublimation from 190 ° C) (Yield: 11%), starting from (benzocyclobutan-1-yl) methyl tosylate and N- (1,2-benzisoxazol-3-yl) piperazine.
  • 7) Le (R,S) 3-{1-[(indan-1-yl) méthyl] pipérazin-4-yl} 1,2-benzisothiazole, P.F. : 88-90°C, (Rendement 30 %), à partir du tosylate d'(indan-1-yl) méthyle et de la N-(1,2-benzisothiazol-3-yl) pipérazine. 7) (R, S) 3- {1 - [(indan-1-yl) methyl] piperazin-4-yl} 1,2-benzisothiazole, mp: 88-90 ° C, (Yield 30%), at from (indan-1-yl) methyl tosylate and N- (1,2-benzisothiazol-3-yl) piperazine.
  • 8) Le (R,S) 3-{1-[(5,6-diméthoxy-indan-1-yl) méthyl] pipérazin-4-yl} 1,2-benzisothiazole, P.F. : 131-133°C (Rendement 3,6%), à partir du tosylate de (5,6-diméthoxy-indan-1-yl) méthyle et de la N-(1,2-benzisothiazol-3-yl) pipérazine.
    Le tosylate de (5,6-diméthoxy-indan-1-yl)méthyle de départ a lui-même été préparé comme suit :
    A 3,1 g d'hydrure de lithium aluminium en suspension dans 30 ml de tétrahydrofurane sont ajoutés 18 g d'acide (5,6-diméthoxy-indan-1-yl)carboxylique [lui-même décrit dans J. Pharm. Sci. (1968) 57 (6) 1013] dissous dans 180 ml de tétrahydrofurane. Après 18 h d'agitation à température ambiante sont ajoutés goutte à goutte en refroidissant 2,2 ml d'eau, puis 1,7 ml de soude à 20 % et enfin 7,6 ml d'eau. Les sels minéraux sont alors filtrés et rincés et le filtrat est evaporé à sec. On obtient ainsi 16,5 g de (5,6-diméthoxy-indan-1-yl) méthanol, sous forme d'huile, avec un rendement de 98 %.
    RMN (solvant : CDCl₃) :
    6,8 ppm, s, 2H ; 3,9 ppm, s, 6H ; 3,8 ppm, d, 2H ;
    3,3 ppm, m, 1H ; 2,9 ppm, m, 2H ; 2,3 ppm, m, 1H ;
    2 ppm, m, 1H ; 1,8 ppm, 1H échangeable.
    Aux 16,5 g de l'alcool précédemment obtenu dissous dans 100 ml de pyridine, sont ajoutés 23,7 g de p.toluènesulfochlorure. Après 18 heures d'agitation à température ambiante, le milieu réactionnel est concentré sous vide . Le résidu obtenu est repris par du chlorure de méthylène puis lavé à l'acide sulfurique normal. Après décantation, la phase organique est séchée puis évaporée à sec. On obtient 31 g de tosylate de (5,6-diméthoxy-indan-1-yl) méthyle, sous forme d'huile, avec un rendement de 97,5 %.
    RMN (solvant : CDCl₃) :
    7,7 ppm, d, 2H ; 7,3 ppm, d, 2H ; 6,7 ppm, 2s, 2H ;
    3,9 à 4,3 ppm, m, 2H ; 3,8 ppm, 2s, 6H ; 3,5 ppm, m 1H ;
    2,8 ppm, m, 2H ; 2,4 ppm, s, 3H ; 2,25 ppm, m, 1H ;
    1,8 ppm, m, 1H.     8) (R, S) 3- {1 - [(5,6-dimethoxy-indan-1-yl) methyl] piperazin-4-yl} 1,2-benzisothiazole, mp: 131-133 ° C (yield 3.6%), from (5,6-dimethoxy-indan-1-yl) methyl tosylate and N- (1,2-benzisothiazol-3-yl) piperazine.
    The starting (5,6-dimethoxy-indan-1-yl) methyl tosylate was itself prepared as follows:
    To 3.1 g of lithium aluminum hydride suspended in 30 ml of tetrahydrofuran are added 18 g of (5,6-dimethoxy-indan-1-yl) carboxylic acid [itself described in J. Pharm. Sci. (1968) 57 (6) 1013] dissolved in 180 ml of tetrahydrofuran. After 18 h of stirring at room temperature are added dropwise while cooling 2.2 ml of water, then 1.7 ml of 20% sodium hydroxide and finally 7.6 ml of water. The mineral salts are then filtered and rinsed and the filtrate is evaporated to dryness. 16.5 g of (5,6-dimethoxy-indan-1-yl) methanol are thus obtained, in the form of an oil, with a yield of 98%.
    NMR (solvent: CDCl₃):
    6.8 ppm, s, 2H; 3.9 ppm, s, 6H; 3.8 ppm, d, 2H;
    3.3 ppm, m, 1H; 2.9 ppm, m, 2H; 2.3 ppm, m, 1H;
    2 ppm, m, 1H; 1.8 ppm, 1H exchangeable.
    To the 16.5 g of the alcohol previously obtained dissolved in 100 ml of pyridine, are added 23.7 g of p.toluenesulfochloride. After 18 hours of stirring at room temperature, the reaction medium is concentrated under vacuum. The residue obtained is taken up in methylene chloride and then washed with normal sulfuric acid. After decantation, the organic phase is dried and then evaporated to dryness. 31 g of methyl (5,6-dimethoxy-indan-1-yl) tosylate are obtained, in the form of an oil, with a yield of 97.5%.
    NMR (solvent: CDCl₃):
    7.7 ppm, d, 2H; 7.3 ppm, d, 2H; 6.7 ppm, 2s, 2H;
    3.9 to 4.3 ppm, m, 2H; 3.8 ppm, 2s, 6H; 3.5 ppm, m 1H;
    2.8 ppm, m, 2H; 2.4 ppm, s, 3H; 2.25 ppm, m, 1H;
    1.8 ppm, m, 1H.
  • 9) Le 3-[1-(indan-2-yl)pipérazin-4-yl] 1,2-benzisothiazole P.F : 158-162 °C, à partir du tosylate d'indan-2-yle et de la N-(1,2-benzisothiazol-3-yl)pipérazine. 9) 3- [1- (indan-2-yl) piperazin-4-yl] 1,2-benzisothiazole PF: 158-162 ° C, from indan-2-yl tosylate and N- (1,2-benzisothiazol-3-yl) piperazine.
  • 10) Le 3- [1-(indan-2-yl)pipérazin-4-yl] 1,2-benzisoxazole et son fumarate P.F : 216-219 °C, à partir du tosylate d'indan-2-yle et de la N-(1,2-benzisoxazol-3-yl) pipérazine. 10) 3- [1- (indan-2-yl) piperazin-4-yl] 1,2-benzisoxazole and its fumarate PF: 216-219 ° C, starting from indan-2-yl tosylate and N- (1,2-benzisoxazol-3-yl) piperazine.
  • 11) Le 3-[1-(indan-2-yl)pipérazine-4-yl] 6-fluoro 1,2-benzisoxazole et son fumarate P.f : 205-208 °C, à partir du tosylate d'indan-2-yle et de la N-(6-fluoro 1,2-benzisoxazol-3-yl) pipérazine. 11) 3- [1- (indan-2-yl) piperazine-4-yl] 6-fluoro 1,2-benzisoxazole and its fumarate Pf: 205-208 ° C, from indan-2- tosylate yl and N- (6-fluoro 1,2-benzisoxazol-3-yl) piperazine.
  • 12) Le (R,S) 3-(1-[(4,5-diméthoxybenzocyclobutan-1-yl)méthyl]pipérazin-4-yl} 1,2-benzisothiazole et son chlorhydrate P.F>260 °C, à partir du tosylate de (4,5-diméthoxybenzocyclobutan-1-yl)méthyle et de la N-(1,2-benzisothiazol-3-yl) pipérazine. 12) (R, S) 3- (1 - [(4,5-dimethoxybenzocyclobutan-1-yl) methyl] piperazin-4-yl} 1,2-benzisothiazole and its hydrochloride PF> 260 ° C, starting from (4,5-dimethoxybenzocyclobutan-1-yl) methyl tosylate and N- (1,2-benzisothiazol-3-yl) piperazine.
  • 13) Le (R,S) 3-{1-[3-(benzocyclobutan-1-yl)propyl]pipérazin-4-yl} 1,2-benzisothiazole et son chlorhydrate P.F>260 °C, à partir du mésylate de 3-(benzocyclobutan-1-yl)propyle et de la N-(1,2-benzisothiazol-3-yl) pipérazine. 13) (R, S) 3- {1- [3- (benzocyclobutan-1-yl) propyl] piperazin-4-yl} 1,2-benzisothiazole and its hydrochloride PF> 260 ° C, starting from mesylate 3- (benzocyclobutan-1-yl) propyl and N- (1,2-benzisothiazol-3-yl) piperazine.
  • 14) Le (R,S) 3-{1-[2-(4,5-diméthoxy benzocyclobutan-1-yl)éthyl]pipérazin-4-yl} 1,2-benzisothiazole et son chlorhydrate P.F : 198-200 °C, à partir du tosylate de 2-(4,5-diméthoxybenzocyclobutan-1-yl) éthyle et de la N-(1,2-benzisothiazol-3-yl) pipérazine. 14) (R, S) 3- {1- [2- (4,5-dimethoxy benzocyclobutan-1-yl) ethyl] piperazin-4-yl} 1,2-benzisothiazole and its hydrochloride PF: 198-200 ° C, from 2- (4,5-dimethoxybenzocyclobutan-1-yl) ethyl tosylate and N- (1,2-benzisothiazol-3-yl) piperazine.
  • 15) Le 3-{1-[(5,6-diméthoxyindan-2-yl) méthyl] pipérazin-4-yl} 1,2-benzisothiazole P.F : 102-105 °C, à partir du tosylate de (5,6-diméthoxyindan-2-yl) méthyle et de la N-(1,2-benzisothiazol-3-yl) pipérazine. 15) 3- {1 - [(5,6-dimethoxyindan-2-yl) methyl] piperazin-4-yl} 1,2-benzisothiazole PF: 102-105 ° C, from tosylate from (5.6 -dimethoxyindan-2-yl) methyl and N- (1,2-benzisothiazol-3-yl) piperazine.
  • 16) Le 3-{1-[(indan-2-yl) méthyl] pipérazin-4-yl} 1,2-benzisothiazole P.F : 88-90 °C, à partir du tosylate d'(indan-2-yl) méthyle et de la N-(1,2-benzisothiazol-3-yl) pipérazine. 16) 3- {1 - [(indan-2-yl) methyl] piperazin-4-yl} 1,2-benzisothiazole PF: 88-90 ° C, from (indan-2-yl) tosylate methyl and N- (1,2-benzisothiazol-3-yl) piperazine.
Exemple 17 : Example 17 : (R,S) 3-{1-[(4,5-diméthoxybenzocyclobutan-1-yl) méthyl] pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole :(R, S) 3- {1 - [(4,5-dimethoxybenzocyclobutan-1-yl) methyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole:

Figure imgb0009
Figure imgb0009

a) première étape :a) first step:

On mélange 2,12 g (1,02.10⁻² mole) d'acide (4,5-diméthoxybenzocyclobutan-1-yl) carboxylique dans 12 ml de chlorure de méthylène et y ajoute, en une seule fois, 1,72 g (1,06.10⁻² mole) de carbonyldiimidazole. On maintient sous agitation pendant une nuit à température ambiante puis ajoute, à la spatule, 2,26 g (1,02.10-2 mole) de N-(6-fluoro 1,2-benzisoxazol-3-yl) pipérazine [préparée selon J.P. YEVICH et Coll. J. Med. Chem. (1986), 29, p 359-369].2.12 g (1.02.10⁻² mole) of (4,5-dimethoxybenzocyclobutan-1-yl) carboxylic acid are mixed in 12 ml of methylene and added thereto, at a single time, 1.72 g (1.06 × 10 -2 mol) of carbonyldiimidazole. The mixture is stirred overnight at room temperature and then added with a spatula 2.26 g (1.02.10-2 mole) of N- (6-fluoro 1,2-benzisoxazol-3-yl) piperazine [prepared according to JP YEVICH et al. J. Med. Chem. (1986), 29 , p 359-369].

Le mélange réactionnel est laissé à température ambiante pendant 48 heures, puis additionné d'eau. Après décantation, la phase organique est lavée à l'eau puis avec une solution de NaHCO₃. Après séchage on obtient une gomme que l'on cristallise dans l'acétate d'éthyle. On obtient alors 2,4 g de (R,S) 3-{1-[(4,5-diméthoxybenzocyclobutan-1-yl) carbonyl] pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole, P.F. : 200°C,
Rendement : 57 %
RMN (solvant : CDCl₃) :
7,65 ppm, 1H (dd) ; 7,15 ppm, 1H (dd) ; 7,05 ppm, 1H (td) ;
6,7 à 6,8 ppm, 2H (2s) ; 4,4 ppm, 1H (t) ; 3,7 à 4 ppm, 4H (m) + 6H (2s) ;
3,65 ppm, 4H (m) ; 3,4 ppm, 2H (d).The reaction mixture is left at room temperature for 48 hours, then added with water. After decantation, the organic phase is washed with water and then with a solution of NaHCO₃. After drying, a gum is obtained which is crystallized from ethyl acetate. 2.4 g of (R, S) 3- {1 - [(4,5-dimethoxybenzocyclobutan-1-yl) carbonyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole, PF: 200 are then obtained. ° C,
Efficiency: 57%
NMR (solvent: CDCl₃):
7.65 ppm, 1H (dd); 7.15 ppm, 1H (dd); 7.05 ppm, 1H (td);
6.7 to 6.8 ppm, 2H (2s); 4.4 ppm, 1H (t); 3.7 to 4 ppm, 4H (m) + 6H (2s);
3.65 ppm, 4H (m); 3.4 ppm, 2H (d).

L'acide (4,5-diméthoxybenzocyclobutan-1-yl) carboxylique de départ a été préparé selon le procédé décrit dans Tétrahedron (1973), 29, p 73.The starting (4,5-dimethoxybenzocyclobutan-1-yl) carboxylic acid was prepared according to the method described in Tétrahedron (1973), 29 , p 73.

b) deuxième étape :b) second step:

Sous atmosphère d'azote, on ajoute 0,26 g (7.10⁻³ mole) d'hydrure de lithium-aluminium à 41 ml de tétrahydrofurane anhydre ; on amène l'ensemble à 30°C puis ajoute, à la spatule, 2,4 g (5,8.10⁻³ mole) de (R,S) 3-{1-[(4,5-diméthoxy benzocyclobutan-1-yl) carbonyl] pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole, précédemment obtenu. On maintient la température du mélange réactionnel à 30°C pendant 8 heures. Puis on refroidit l'ensemble et l'hydrolyse avec 0,9 ml d'eau et 0,15 ml de solution d'hydroxyde de sodium à 20 %. Après filtration des sels et décantation du mélange réactionnel, on lave la phase organique à l'eau puis la sèche sur MgSO₄. Après chromatographie sur silice en éluant avec le mélange chlorure de méthylène/acétate d'éthyle (90/10), puis recristallisation dans 4,5 ml d'acétate d'éthyle, on obtient 0,63 g de (R,S) 3-{1-[(4,5-diméthoxybenzocyclobutan-1-yl) méthyl] pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole, P.F. : 141-143°C, Rendement : 27 %.
RMN (solvant : CDCl₃) :
7,65 ppm, 1H (dd) ; 7,15 ppm, 1H (dd) ; 6,95 ppm, 1H (td) ;
6,7 ppm, 2H (2s) ; 3,85 ppm, 6H (s) ; 3,6 ppm, 5H (m) ;
3,3 ppm, 1H (dd) ; 2,6 à 3 ppm, 1H (dd) + 2H (m) + 4H (m).Under a nitrogen atmosphere, 0.26 g (7.10⁻³ mole) of lithium aluminum hydride is added to 41 ml of anhydrous tetrahydrofuran; the whole is brought to 30 ° C. and then added, with a spatula, 2.4 g (5.8.10⁻³ mole) of (R, S) 3- {1 - [(4,5-dimethoxy benzocyclobutan-1- yl) carbonyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole, previously obtained. The temperature of the reaction mixture is maintained at 30 ° C for 8 hours. The whole is then cooled and hydrolyzed with 0.9 ml of water and 0.15 ml of 20% sodium hydroxide solution. After filtration of the salts and decantation of the reaction mixture, the organic phase is washed with water and then dried over MgSO₄. After chromatography on silica, eluting with a methylene chloride / ethyl acetate mixture (90/10), then recrystallization from 4.5 ml of ethyl acetate, 0.63 g of (R, S) 3 is obtained. - {1 - [(4,5-dimethoxybenzocyclobutan-1-yl) methyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole, mp: 141-143 ° C, yield: 27%.
NMR (solvent: CDCl₃):
7.65 ppm, 1H (dd); 7.15 ppm, 1H (dd); 6.95 ppm, 1H (td);
6.7 ppm, 2H (2s); 3.85 ppm, 6H (s); 3.6 ppm, 5H (m);
3.3 ppm, 1H (dd); 2.6 to 3 ppm, 1H (dd) + 2H (m) + 4H (m).

De la même façon ont été préparés les dérivés objets des exemples 18 à 20.In the same way, the derivatives object of Examples 18 to 20 were prepared.

Exemples 18 - 20Examples 18-20

  • 18) Le (R,S) 3-{1-[(indan-1-yl)méthyl] pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole, P.F. : 109-111°C, (rendement : 28 %), à partir de (R,S) 3-{1-[(indan-1-yl)carbonyl] pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole, P.F. : 151°C, lui-même préparé, avec un rendement de 55 %, à partir d'acide indan-1-yl carboxylique et de N-(6-fluoro 1,2 benzisoxazol-3-yl) pipérazine. 18) (R, S) 3- {1 - [(indan-1-yl) methyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole, mp: 109-111 ° C, (yield: 28 %), from (R, S) 3- {1 - [(indan-1-yl) carbonyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole, mp: 151 ° C, itself prepared, with a yield of 55%, from indan-1-yl carboxylic acid and N- (6-fluoro 1,2 benzisoxazol-3-yl) piperazine.
  • 19) Le (R,S) 3-{1-[(4,5-diméthoxybenzocyclobutan-1-yl) méthyl] pipérazin-4-yl} 1,2-benzisoxazole, P.F. : 136-139°C, (Rendement : 52 %), à partir de (R,S) 3-{1-[(4,5-diméthoxybenzocyclobutan-1-yl) carbonyl] pipérazin-4-yl} 1,2-benzisoxazole, P.F. : 165°C, lui-même préparé, avec un rendement de 80 %, à partir d'acide (4,5-diméthoxybenzocyclobutan-1-yl) carboxylique et de N-(1,2-benzisoxazol-3-yl) pipérazine. 19) Le (R, S) 3- {1 - [(4,5-dimethoxybenzocyclobutan-1-yl) methyl] pipérazin-4-yl} 1,2-benzisoxazole, mp: 136-139 ° C, (Yield: 52%), starting from (R, S) 3- {1 - [(4,5-dimethoxybenzocyclobutan-1-yl) carbonyl] pipérazin-4-yl} 1,2-benzisoxazole, mp: 165 ° C, - even prepared, with a yield of 80%, from (4,5-dimethoxybenzocyclobutan-1-yl) carboxylic acid and N- (1,2-benzisoxazol-3-yl) piperazine.
  • 20) Le (R,S) 3-{1-[(indan-1-yl) méthyl] pipérazin-4-yl} 1,2-benzisoxazole, P.F. : 83-86°C, (Rendement : 44 %), à partir de (R,S) 3-{1-[(indan-1-yl) carbonyl] pipérazin-4-yl} 1,2-benzisoxazole, P.F. : 114°C, lui-même préparé, avec un rendement de 80 %, à partir d'acide indan-1-yl carboxylique et de N-(1,2-benzisoxazol-3-yl) pipérazine. 20) Le (R, S) 3- {1 - [(indan-1-yl) methyl] pipérazin-4-yl} 1,2-benzisoxazole, mp: 83-86 ° C, (Yield: 44%), from (R, S) 3- {1 - [(indan-1-yl) carbonyl] piperazin-4-yl} 1,2-benzisoxazole, mp: 114 ° C, itself prepared, with a yield of 80%, from indan-1-yl carboxylic acid and N- (1,2-benzisoxazol-3-yl) piperazine.
Exemple 21 : Example 21 : Etude pharmacologique.Pharmacological study. Test des stéréotypies induites par le méthylphénidate chez le rat : Methylphenidate-induced stereotypy test in rats :

Pour cet essai, on a utilisé 24 rats Wistar mâles, d'un poids compris entre 220 et 240 g, à jeun depuis environ 24 heures. Chaque animal reçoit un premier traitement (composé de référence, dérivé de l'invention ou solvant) à un temps déterminé avant un deuxième traitement (méthylphénidate ou sérum physiologique) effectué par voie I.P. au temps nommé T₀. Parmi les animaux utilisés lors d'un essai, quatre servent de contrôle et reçoivent les traitements suivants :
sérum + sérum I.P. : 1 animal (contrôle sérum) ; solvant + méthylphénidate à 40 mg/kg I.P. : 2 animaux (contrôle méthylphénidate à 40 mg/kg I.P.) et solvant + méthylphénidate à 0,16 ; 0,63 ; 2,5 ou 10 mg/kg I.P. : 1 animal (contrôles méthylphénidate 0,16 ; 0,63 ; 2,5 ou 10 mg/kg I.P.).For this test, 24 male Wistar rats, weighing between 220 and 240 g, were used on an empty stomach for approximately 24 hours. Each animal receives a first treatment (reference compound, derivative of the invention or solvent) at a determined time before a second treatment (methylphenidate or physiological saline) carried out by IP route at the time designated T₀. Among the animals used in a test, four serve as controls and receive the following treatments:
serum + IP serum: 1 animal (serum control); solvent + methylphenidate at 40 mg / kg PI: 2 animals (methylphenidate control at 40 mg / kg PI) and solvent + methylphenidate at 0.16; 0.63; 2.5 or 10 mg / kg PI: 1 animal (methylphenidate controls 0.16; 0.63; 2.5 or 10 mg / kg PI).

Les produits étudiés ont été administrés à des temps donnés avant l'injection à T₀ de 40 mg/kg I.P. de méthylphénidate. Chaque animal est observé pendant 10 secondes. Les observations comportementales ont eu lieu 30 minutes après le traitement au méthylphénidate. Un total de 10 périodes d'observation est réalisé pour chaque rat au temps T₃₀ mn. Pendant ces observations, la présence (1) ou l'absence (0) de stéréotypie est notée.The products studied were administered at given times before injection at T₀ of 40 mg / kg I.P. of methylphenidate. Each animal is observed for 10 seconds. Behavioral observations were made 30 minutes after the methylphenidate treatment. A total of 10 observation periods are carried out for each rat at time T₃₀ mn. During these observations, the presence (1) or absence (0) of stereotypy is noted.

L'analyse statistique a consisté à comparer, pour une stéréotypie donnée, les taux des scores (0 à 10) obtenus par un groupe d'animaux ayant reçu le même traitement, à ceux obtenus par le groupe d'animaux contrôles méthylphénidate 40 mg/kg, selon le test de Mann et Whitney avec la signification p = 0,05 (cf Siegel S et Castelan N.J. 1988).The statistical analysis consisted in comparing, for a given stereotype, the rates of the scores (0 to 10) obtained by a group of animals having received the same treatment, with those obtained by the group of control animals methylphenidate 40 mg / kg, according to the Mann and Whitney test with the meaning p = 0.05 (see Siegel S and Castelan NJ 1988).

A titre d'exemple d'évaluation de l'activité antipsychotique des produits de la présente invention, sont répertoriées dans le tableau ci-après les doses efficaces moyennes (ED₅₀), c'est à dire les doses permettant une inhibition de 50 % du mâchonnement.

Figure imgb0010
As an example of evaluation of the antipsychotic activity of the products of the present invention, the average effective doses (ED₅₀) are listed in the table below, that is to say the doses allowing a 50% inhibition of the chewing.
Figure imgb0010

Claims (18)

1) Les dérivés de benzisoxazole et de benzisothiazole de formule générale I :
Figure imgb0011
 dans laquelle: - X₁, X₂, X₃, X₄ et X₅ : - identiques ou différents représentent chacun : un atome d'hydrogène, un atome d'halogène, un radical alkyle, alkoxy ou alkythio dans chacun desquels la partie alkyle renferme de 1 à 5 atomes de carbone en chaine droite ou ramifiée, un radical hydroxy, un radical acyloxy, un radical trifluorométhyle, un radical nitro, un radical amino ou un radical acétamido, ou - deux d'entre eux pris en position adjacente forment ensemble un radical méthylènedioxy, un radical éthylènedioxy ou un radical vinylènedioxy ; - R₁ représente un atome d'hydrogène ou un radical alkyle en chaine droite ou ramifiée contenant de 1 à 5 atomes de carbone ; - m et n représentent chacun les valeurs zéro, un, deux ou trois à condition que m + n soit ≧ 1 ; - p représente zéro ou un nombre entier de 1 à 6 ; - q représente deux ou trois, et - Y représente un atome d'oxygène ou le groupe S(O)z dans lequel z prend les valeurs zéro, un ou deux ;
sous forme racémique et optiquement actives. 1) The benzisoxazole and benzisothiazole derivatives of general formula I:
Figure imgb0011
 in which: - X₁, X₂, X₃, X₄ and X₅: - identical or different, each represents: a hydrogen atom, a halogen atom, an alkyl, alkoxy or alkythio radical in each of which the alkyl part contains from 1 to 5 carbon atoms in a straight or branched chain, a hydroxy radical, an acyloxy radical, a trifluoromethyl radical, a nitro radical, an amino radical or an acetamido radical, or - two of them taken in adjacent position together form a methylenedioxy radical, an ethylenedioxy radical or a vinylenedioxy radical; - R₁ represents a hydrogen atom or an alkyl radical in a straight or branched chain containing from 1 to 5 carbon atoms; - m and n each represent the values zero, one, two or three provided that m + n is ≧ 1; - p represents zero or an integer from 1 to 6; - q represents two or three, and - Y represents an oxygen atom or the group S (O) z in which z takes the values zero, one or two;
in racemic and optically active form. 2) Les sels physiologiquement tolérables des dérivés de la revendication 1 avec des acides appropriés. 2) The physiologically tolerable salts of the derivatives of claim 1 with suitable acids. 3) Le (R,S) 3-{1-[(benzocyclobutan-1-yl) méthyl] pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole, et son chlorhydrate. 3) (R, S) 3- {1 - [(benzocyclobutan-1-yl) methyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole, and its hydrochloride. 4) Le (R,S) 3-{1-[4-(benzocyclobutan-1-yl)butyl]pipérazin-4-yl}1,2-benzisothiazole et son chlorhydrate. 4) (R, S) 3- {1- [4- (benzocyclobutan-1-yl) butyl] piperazin-4-yl} 1,2-benzisothiazole and its hydrochloride. 5) Le (R,S) 3-{1-[(benzocyclobutan-1-yl) méthyl] pipérazin-4-yl} 1,2-benzisoxazole, et son chlorhydrate. 5) (R, S) 3- {1 - [(benzocyclobutan-1-yl) methyl] piperazin-4-yl} 1,2-benzisoxazole, and its hydrochloride. 6) Le 3-[1-(indan-2-yl)pipérazin-4-yl] 6-fluoro 1,2-benzisoxazole et son fumarate. 6) 3- [1- (indan-2-yl) piperazin-4-yl] 6-fluoro 1,2-benzisoxazole and its fumarate. 7) Le (R,S) 3-{1-[3-(benzocyclobutan-1-yl)propyl] pipérazin-4-yl} 1,2-benzisothiazole et son chlorhydrate. 7) (R, S) 3- {1- [3- (benzocyclobutan-1-yl) propyl] piperazin-4-yl} 1,2-benzisothiazole and its hydrochloride. 8) Le 3-{1-[(5,6-diméthoxyindan-2-yl) méthyl] pipérazin-4-yl} 1,2-benzisothiazole. 8) 3- {1 - [(5,6-dimethoxyindan-2-yl) methyl] piperazin-4-yl} 1,2-benzisothiazole. 9) Le (R,S)) 3-{1-[4,5-diméthoxybenzocyclobutan-1-yl)méthyl] pipérazin-4-yl} 6-fluoro 1,2-benzisoxazole. 9) Le (R, S)) 3- {1- [4,5-dimethoxybenzocyclobutan-1-yl) methyl] piperazin-4-yl} 6-fluoro 1,2-benzisoxazole. 10) Le (R,S) 3-{1-[4,5-diméthoxybenzocyclobutan-1-yl)méthy1] pipérazin-4-yl} 1,2-benzisoxazole. 10) Le (R, S) 3- {1- [4,5-dimethoxybenzocyclobutan-1-yl) methyl1] piperazin-4-yl} 1,2-benzisoxazole. 11) Le procédé de préparation des dérivés de la revendication 1 caractérisé en ce que l'on condense : - un dérivé de formule générale II :
Figure imgb0012
 dans laquelle q, Y, X₄ et X₅ ont les significations définies dans la revendication 1,
avec - un dérivé de formule générale III :
Figure imgb0013
dans laquelle : - X₁, X₂, X₃, R₁, m, n et p ont les significations définies dans la revendication 1, et- X représente un atome d'halogène, un radical mésyloxy ou un radical tosyloxy. 11) The process for preparing the derivatives of claim 1 characterized in that one condenses: - a derivative of general formula II:
Figure imgb0012
 in which q, Y, X₄ and X₅ have the meanings defined in claim 1,
with - a derivative of general formula III:
Figure imgb0013
in which : - X₁, X₂, X₃, R₁, m, n and p have the meanings defined in claim 1, and X represents a halogen atom, a mesyloxy radical or a tosyloxy radical. 12) Le procédé de préparation selon la revendication 11 caractérisé en ce que l'on effectue la condensation des dérivés II et III dans un solvant approprié, à une température comprise entre 20 et 150°C, en présence d'un accepteur de l'acide formé au cours de la réaction. 12) The preparation process according to claim 11 characterized in that the condensation of derivatives II and III is carried out in an appropriate solvent, at a temperature between 20 and 150 ° C, in the presence of an acceptor of the acid formed during the reaction. 13) Le procédé de préparation des dérivés de la revendication 1 répondant à la formule générale I′ :
Figure imgb0014
 dans laquelle : - X₁, X₂, X₃, X₄, X₅, R₁, m, n, q et Y ont les significations définies dans la revendication 1, et - p′ représente un nombre entier de 1 à 6, caractérisé en ce que : - l'on condense : - un dérivé de formule générale II définie dans la revendication 11,
avec, - un dérivé de formule générale IV :
Figure imgb0015
 dans laquelle X₁, X₂, X₃, X₄, X₅, R₁, m, n et p′ ont les significations précédemment défines ; et - l'on réduit l'amide ainsi obtenu de formule générale V :
Figure imgb0016
 dans laquelle X₁, X₂, X₃, X₄, X₅, R₁, m, n, p′, q et Y ont les significations précédemment définies. 13) The process for the preparation of the derivatives of claim 1 corresponding to the general formula I ′:
Figure imgb0014
 in which : - X₁, X₂, X₃, X₄, X₅, R₁, m, n, q and Y have the meanings defined in claim 1, and - p ′ represents an integer from 1 to 6, characterized in that: - we condense: - a derivative of general formula II defined in claim 11,
with, - a derivative of general formula IV:
Figure imgb0015
 in which X₁, X₂, X₃, X₄, X₅, R₁, m, n and p ′ have the meanings previously defined; and the amide thus obtained of general formula V is reduced:
Figure imgb0016
 in which X₁, X₂, X₃, X₄, X₅, R₁, m, n, p ′, q and Y have the meanings previously defined. 14) Le procédé de préparation selon la revendication 13 caractérisé en ce que l'on effectue la condensation des dérivés II et IV dans le chlorure de méthylène en présence de carbonyldiimidazole. 14) The preparation process according to claim 13 characterized in that the condensation of derivatives II and IV is carried out in methylene chloride in the presence of carbonyldiimidazole. 15) Le procédé de préparation selon les revendications 13 et 14 caractérisé en ce que l'on effectue la réduction de l'amide V au moyen d'un hydrure double de lithium-aluminium dans un solvant approprié. 15) The preparation process according to claims 13 and 14 characterized in that the reduction of amide V is carried out by means of a double lithium aluminum hydride in an appropriate solvent. 16) A titre de produits intermédiaires nouveaux utilisables dans la synthèse des dérivés I′ selon la revendication 13, les amides de formule générale V :
Figure imgb0017
 dans laquelle X₁, X₂, X₃, X₄, X₅, R₁, m, n, p′, q et Y ont les significations définies dans la revendication 11. 16) As new intermediate products which can be used in the synthesis of derivatives I ′ according to claim 13, the amides of general formula V:
Figure imgb0017
 in which X₁, X₂, X₃, X₄, X₅, R₁, m, n, p ′, q and Y have the meanings defined in claim 11. 17) Les compositions pharmaceutiques contenant commme principe actif un dérivé selon les revendications 1 à 10 avec des excipients pharmaceutiques appropriés. 17) The pharmaceutical compositions containing as active ingredient a derivative according to claims 1 to 10 with suitable pharmaceutical excipients. 18) Les compositions pharmaceutiques selon la revendication 17, présentées sous une forme convenant notamment pour le traitement de la douleur, l'anxiété, la psychose, la schizophrénie et la dépression. 18) The pharmaceutical compositions according to claim 17, presented in a form suitable in particular for the treatment of pain, anxiety, psychosis, schizophrenia and depression.
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